Wednesday, 31 August 2016

A lot of work needs to be done to activate MSers to become more engaged in their treatments. #MSBlog #SurveySpeak #ClinicSpeak"Many thanks to those of you who completed yesterday's lymphopaenia survey. The results indicate that too few of you are engaged with your pharmacovigilance. You need to engage in tracking your own blood and urine results and understand why you are doing this and the reasons for the frequency of testing. I would expect nothing less from an expert patient. In addition to pharmacovigilance it is also time that you engaged with the tracking of your own disease activity. Please remember information is power and the more information you have about your treatment and its monitoring the more power you will have over your own health and the ability to optimise it. We are entering an era when the activated patient is the change agent that will catalyse the revolution we need in healthcare delivery and consumption; you simply can't rely on the medical profession to do this. Trust me when I say, the medical profession is one of the most resistant professions when it comes to change and the adoption of new innovations."

Last year we there was a buzz at ECTRIMS about ocrelizumab and this year it may well be Siponimod and its influence on secondary progressive MS. This is to be presented at the late breaking session at ECTRIMS 2016.

Is this a game changer?

The disruptor for MS pharma, is fingolimod coming-off patent in 2019. With the development of generics the price tumbles (except that MS pharma control a number of generic companies :-)

However, does the success of siponimod mean that people in power are happy that fingolimod failed in PPMS? Had it been a success could they have protected the PPMS market, whilst the RRMS fell to generic competitors?

As fingo is second line surely Sipo will get a first line label now. This is because the climate has changed since fingo was approved and got a second line label (It was expensive and had side effects), as alemtuzumab exceeds this on price and side-effects but that has a first line label (in UK).

Siponimod has succeeded in relapsing MS in early trials just like fingo other all other fingo me too's and now with some success in SPMS. Why go for fingo when you could have sipo to cover RR and SP bases?

Was this the master plan?

However, will this be a game changer?

First we have to know is whether it is really progression that is being targeted or has the trial been loaded with relapsing people with SPMS? If I was designing a trial I would load it with people with lower levels of EDSS and have as many gadolinium enhancing subjects in the mix. We know that relapsing MS/MRI activity contributes to damage and we know that this responses to Spingosine-1-phosphate modulators?

We will have to wait and see the data. It will be the first question everyone asks but I suspect that "the data is still being analysed".

Answers to this may help define the battle ground with ocrelizumab.

Is Siponimod the first drug to have an effect on progressive MS? However, will we have deja vu and just as oral cladribine stumbled at the last hurdle to be beaten by Fingolimod, will siponimod be pipped or pip ocrelizumab to the final progressive hurdle?

Will the regulators buy the idea that ocrelizumab was active for all of progression, rather than just working in active (MRI positive relapsing) progression? I suspect the data has been collected in such a way that it will be impossible to answer as there were probably not enough scans to work out if lesions occurred after the initial negative scans. I personally think this will be a tough ask, but can the regulators be hood-winked? Importantly will the cancers that popped up (nine verses 0 in placebo) in the ocrelizumab progressive trial, do it in just like it did for oral cladribine (three verse 0 in placebo. You say there were more in the original publication but some turned out not to be cancer). I suspect one pharma may be lobbying hard for the bad view to be upheld. Maybe the additional RRMS studies will change the view of the regulators, but if the regulators are of the blinkered-phenotype which seems par for the course for reviewers then there will be problems, I suspect. I hope not

However, the other issue of a successful progressive MS drug, may mean that trials, like the MS-SMART may not be so smart, because if there is a positive result, pharma will surely insist that any drug that is positive in academic studies undergo the same rigour of the process that pharma are made to do.The academic trials will not have that level of support and it would be terrible if the studies stalled at the end of phase III.

Will it now be worth pursuing the simvastatin story which will take many years to complete, because doctors will be encouraged to prescribe the licensed option?

However, we may get some insight into MS-SMART as results of using prozac in progressive MS are being presented at ECTRIMS 2016.

Anyway, one further nail in the EAE coffin as one more aspect of MS appears to get a solution. But how does it do this ?

CoI None....ProfG may know the answers already and take a different view

BACKGROUND:Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1, 5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE.METHODS: Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells.RESULTS: Siponimod administration (0.45 μg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission.CONCLUSIONS:Altogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.

Given the recent news that Siponimod has a beneficial effect in secondary progressive MS to be presented at ECTRIMS 2016 hot topic session is going to be one of the hightlights of the meeting one suspects. This animal study suggests that it may have some benefit in saving nerves

Tuesday, 30 August 2016

Do you have a normal lymphocyte count? Do you know your lymphocyte counts? #ResearchSpeak #MSBlog #MSResearch

"The retrospective study below found that 1 in 10 DMT-naive MSers had low lymphocyte counts and in the majority of these no obvious cause could be found. The authors' suggest the lymphopaenia is due to autoimmunity, or is stress-induced through increased cortisol production or Epstein-Barr activation.""I live and learn something new every day of the week about MS. I had no idea that ~10% of MSers had idiopathic (no apparent cause found) lymphopaenia. What is interesting that in this study low lymphocyte counts at baseline predicted low lymphocyte counts on treatment. Clearly these findings needs to be confirmed and explained. Who knows it may provide interesting insights into the pathogenesis of MS. I like the suggestion that it may be linked to stress and/or EBV reactivation."

"Lymphopaenia is one of the key battlegrounds in the marketing of DMTs. Low lymphocyte counts are an important risk factor for several serious adverse events on DMTs. Understanding MS-related lymphopaenia may help de-risk some of these DMTs. I am interested to know how many of you know what your latest lymphocyte counts are? If you don't you should find out and keep a record of it for yourself."

A lymphocyte: image source Wikipedia

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Lim et al. Lymphopenia in treatment-naive relapsing multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016 Aug 12;3(5):e275. doi: 10.1212/NXI.0000000000000275. eCollection 2016.Background: Lymphopenia accompanies some autoimmune diseases. Several studies, but not others, have suggested that lymphopenia occurs in treatment-naive multiple sclerosis (MS), so the issue remains unresolved.Methods: Data were collected retrospectively during an institutionally approved service evaluation of blood test monitoring of patients with relapsing MS in a regional MS service in Southampton, UK, over a 2-year period (2012–2014). Control lymphocyte data were derived from preoperative blood counts of age- and sex-matched individuals undergoing septoplasty in the same hospital for structural reasons, excluding neoplastic and infective operative indications.

Results: Seven hundred sixty-four patients were identified with blood test data (table). Baseline and post-treatment blood tests were available in 466 and 247 patients, respectively. Average blood test frequency was 4 per year. Lymphocyte counts were relatively stable with time, with a coefficient of variation of 7.5%. The mean lymphocyte count in treatment-naive patients with MS was 2.18 × 109/L with an SD of 0.66 × 109. Lymphopenia was present in 10% (48 patients; 46 grade I, one grade II, one grade III). In only 3 cases steroids were administered in the month before lymphopenia. There was no association between pretreatment lymphocyte count and any patient characteristic or month or season.

Discussion: Since the lymphocyte reference range covers 95% of values in a healthy population, lymphopenia is expected in 2.5%. In our treatment-naive relapsing MS population, we found lymphopenia in 10%. Moreover, lymphopenia was not associated with relapsing activity. Hence, the lymphopenia in patients with MS is unlikely to be related to autoimmunity. A more likely explanation is stress-induced lymphopenia in both cohorts, through cortisol or Epstein-Barr activation.

"Immunometabolism and autoimmunity".

A continuous increase in the prevalence of autoimmune diseases is to be expected in the aging societies world-wide. Autoimmune disorders not only cause severe disability and chronic pain, but also lead to considerable socio-economic costs. Given that current treatment options are not curative, have substantial side effects and a high percentage of non-responders, innovative options to the existing therapeutic armament against autoimmune diseases are urgently required. Accumulating evidence suggests that changes in the metabolism of immune cells are associated with and contribute to the pathogenesis of autoimmunity. Additionally, some autoimmune diseases share alterations in metabolic pathways, key metabolites or metabolic byproducts such as reactive oxygen species. Other examples for metabolic changes in autoimmune settings include modifications in amino acid and cholesterol levels or glucose catabolism. Thus, the emerging field of immunometabolism may hold the potential to discover new therapeutic targets. Here, we discuss recent findings describing metabolic changes in autoimmune arthritis, multiple sclerosis.

Mounting an immune response requires changes to metabolic processes (i.e. the chemical transformations that are needed for survival). Immune cells have different metabolic requirements depending on their activation state (in order to meet the demands of the activation state) and differentiation state (into effector T cells, which include helper, cytotoxic or regulatory T cells).

Points of metabolic dysregulation in immune function may prove to be therapeutic targets of the future. For example, the natural antioxidant from the green tea plant, EGCG has been shown to promote suppressive Treg cells whilst inhibiting Th1/Th17 formation (proinflammatory cells). This is currently being evaluated in a clinical trial in MS (Sunphenon in progressive forms of multiple sclerosis, NCT00799890).

Leptin is another. Also popularly known as the anti-obesity hormone, leptin has been found to promote CD4 T cell expansion as well as secretion of proinflammatory molecules, such as TNFalpha. Levels of leptin have been sound to be elevated in MS, leading to activation of leptin-mTOR pathway in suppressive Treg cells and as a consequence their impaired expansion. For therapeutic purposes rapamycin-mediated blockade of mTOR activation facilitates Treg expansion and significantly ameliorates EAE (the murine version of MS). Current clinical trials in MS are NCT00228397 (Temsirolimus) and NCT00095329 (Sirolimus).

Statins which lower cholesterol have been proven to be beneficial in MS by inhibiting the formation of proinflammatory Th1 and Th17 responses but favouring Treg responses. In fact the MS-STAT (NCT00647348) showed benefits with regard to brain atrophy measures in SPMS.

These therapeutic targets may therefore prove to be highly attractive options in the near future.

Monday, 29 August 2016

How do you feel about research, or academic, IMPACT? It is a sad fact of life in the modern university. #SurveySpeak #MSBlog "One of our successes this year has been our medical school investing in Alison Thomson our designer; she has officially been appointed as a lecturer. This is the first time our University has embedded a designer within a biomedical research environment. As always we need to justify our existence; this means metrics and impact. We now have to build a case for Alison's work having impact. It would help us enormously if you could please complete a short survey (9 questions and ~1 minute of your time) to help show that Alison's work in relation to the Barts-MS Blog is having impact. The survey is not only for people with MS, but anyone who reads this blog. Thank you!"

Background: This
paper reports early results from a clinical trial evaluating a new drug for relapsing-remitting
Multiple Sclerosis (MS)1. The drug – daclizumab – is a designer
antibody manufactured to dampen down the activity of the immune system by
inhibiting a signal called interleukin-2. In Multiple Sclerosis, the immune
system goes awry and attacks cells in the brain. For this reason, several
clinical trials are looking at whether daclizumab is a safe and effective
treatment for MS. The available evidence suggests that daclizumab is effective2-4,
but is it safe to use in the long term?

Methods: The
SELECTED trial aimed to answer this question. Researchers followed 410 patients
across 8 countries who received 150mg of subcutaneous daclizumab injections
every 4 weeks. On average, the patients had been receiving the treatment for
just over 2 years. It follows on from two earlier trials, SELECT and SELECTION,
which were mainly interested in the effectiveness of daclizumab.

Results: Over
the 3-year study period, 76% experienced an adverse event of some kind. 26%
experienced serious adverse events, of which the most common were MS relapse,
disturbances of liver function, pneumonia, and ulcerative colitis. 12% of
patients experienced an adverse event which led them to stop receiving the
treatment, but no patients died during the study period. It is important to
note that the chance of experiencing a side effect with daclizumab may be
slightly underestimated by these results. This is because patients were
excluded from the trial if they had already left because of a previous adverse
event.

Conclusion: The
take home message of the SELECTED trial is that daclizumab appears to have a
similar risk-benefit profile to commonly-used MS drugs such as beta-interferon.
However, we will have to wait a few more years until the end of the 8-year
study period to confirm that daclizumab is safe for clinical use. We will also
need to find out how daclizumab compares to other drugs in head-to-head trials
looking at long-term safety and efficacy.

BACKGROUND: Patients with multiple sclerosis (MS) or Crohn's disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes.METHODS:The Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects.RESULTS:A total of 369 patients with MS and 7 patients with CD were enrolled, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3-12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9-8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g.CONCLUSIONS: Although the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population.

If you are planning to start a family make sure that you consult with your MS team for advice and monitioring of your treatment status

Background: Multiple
Sclerosis (MS) often starts as an individual episode of neurological
dysfunction. At this early stage, termed a clinically isolated syndrome (CIS),
it is often difficult to predict who will go on to develop definite MS, and who
will have no further episodes. Previous trials have shown that early treatment
with disease-modifying therapies like interferon β-1b can delay the conversion
from CIS to clinically-definite MS. However, it is not known whether early
treatment reduces disability and disease progression in the long-term.

Aim: To assess the effect
of early vs. delayed treatment on long-term outcomes at 11 years after onset of
CIS.

Method: The initial
BENEFIT trial was a randomised, double-blind, placebo-controlled trial in which
participants received either early (n=292) or delayed (n=176) treatment with
interferon β-1b after onset of CIS. The early treatment group began treatment
within 60 days of onset. The delayed treatment group received placebo until
either 2 years after onset of CIS or onset of clinically-definite MS.

After the
initial 2 year trial, patients were invited to participate in a 3-year
open-label extension. In the 3 year extension period, patients could choose to
have any disease-modifying drug/s, or to have no drugs at all. Patients and investigators were not blinded to treatments in this stage.

The 11 year
follow-up study reassessed patients who were part of the original trial 11
years after onset of CIS. 278 of the original 468 patients were assessed. This
was a cross-sectional, observational study that compared several outcome
measures in the early vs delayed treatment groups. The outcomes measured were: risk
of conversion to clinically-definite MS, time to conversion, relapse rate,
conversion to secondary progressive MS, disability scores, neuropsychometric
scores, MRI appearance, and health resource utilisation.

Results: Patients in the
early treatment group had a lower risk of conversion to clinically definite MS (66.6%
vs 75.0%), a longer lag time until the conversion to clinically definite MS, a
lower average annualised relapse rate over the whole study period (0.21 vs 0.26),
and appeared to have a lower risk of conversion to secondary progressive MS (4.5% vs 8.3%). Average
EDSS scores were similar in the early and delayed treatment groups.

The early
treatment group performed better on the Paced Auditory Serial Addition Task-3
(PASAT-3), in which patients have to add up a series of numbers presented to
them via audio at 3-second intervals. There was little difference between early
and delayed treatment groups’ MRI appearances or health resource utilisation.

Conclusion: Early treatment (within
6 months) of CIS with interferon β-1b leads to clinical benefit over delayed
treatment, and this benefit is sustained 11 years after the onset of CIS.

Interpretation: This impressive
study provides a fascinating insight into the long-term consequences of
different treatment strategies in early MS/CIS. What these results appear to
show is that an aggressive, ‘see and treat’, approach in CIS is better than a ‘watch
and wait’ strategy. We knew already from previous incarnations of BENEFIT that early
interferon β-1b treatment delays the onset of and reduces the risk of
conversion to clinically-definite MS. This 11 year follow-up allows us to work
out whether these benefits actually translate into better long-term quality of
life for patients.

It is therefore
interesting that EDSS scores – a commonly-used measure of disability in MS –
were almost identical in the early and delayed treatment groups. This implies
that while early treatment may stave off the onset of definite MS, it does not improve
long-term disability. There are several possible explanations for this finding.
Firstly, the EDSS scores are very low and stable in the study population, and
so the study might not be sufficiently powered to detect small differences
between the groups. Even still, a small difference in EDSS scores, which might
be missed if the study were underpowered, would not necessarily be clinically significant.
A biological explanation for the lack of obvious benefit in terms of EDSS score
is that the processes involved in disability progression in MS, such as
neuronal and synaptic loss, might be quite separate to the processes
responsible for relapses.

Another interesting
observation is that whilst the overall annualised relapse rate (ARR) was lower
in the early treatment group, the ARR was actually slightly lower in the
delayed treatment group in the final year of follow-up. This might imply that
early treatment produces a long-term but not indefinite reduction in relapse
rate, which levels off by year 11. Intuitively, this makes sense, as the
participants spent 9 years on whatever treatment they and their doctors opted
for, and only 2 years in the stringent, double-blind study period.

Given that
participants had received 9 years of treatment since the original study period,
it is remarkable that there were sustained benefits of early treatment in terms
of overall ARR, risk of conversion to clinically-definite MS, time to
conversion, and risk of secondary progressive MS. This could be interpreted as
evidence that there is a crucial window of opportunity when patients have their
first episode suggestive of MS, and that initiating treatment at this stage
produces long-lasting benefits.

On balance,
there seems to be little harm in starting CIS treatment as early as possible.
However, BENEFIT-11 provides no evidence that this approach leads to long-term
differences in disability, the outcome which probably matters most for quality
of life. It does provide some evidence that early treatment influences the
course of the disease, but this is very difficult to disentangle from effects
of other treatment which patients may have tried in the intervening follow-up
period.

BACKGROUND: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with interferon beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a.METHODS: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori.RESULTS: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (all AR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation.CONCLUSIONS: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence.

The Delphi method is a structured communication method, originally developed as a systematic, interactive forecasting method which relies on a panel of experts. The experts answer questionnaires in two or more rounds.After each round, a facilitator provides an anonymous summary of the experts’ forecasts from the previous round as well as the reasons they provided for their judgments. Thus, experts are encouraged to revise their earlier answers in light of the replies of other members of their panel. It is believed that during this process the range of the answers will decrease and the group will converge towards the "correct" answer. Finally, the process is stopped after a predefined stop criterion (e.g. number of rounds, achievement of consensus, stability of results) and the mean or median scores of the final rounds determine the results.

It is not my job to make comment on the findings but they may help you if you are using interferons and maybe one of the neuros may comment on this

How healthy is your lifestyle? Have you optimised your brain health? #BrainHealth #ClinicSpeak"The cross-sectional study below suggests moderate-to-high exercise, moderate alcohol consumption, plant-based omega 3 supplementation and disease-modifying medication are all associated with less disability in MSers. Chicken or egg? A knee jerk response would be that it is obvious that all these lifestyle factors must be affecting the natural history of MS. However, with the exception of DMTs we don't have class one evidence that this is the; by class 1 evidence I mean randomised blinded intervention studies. These observations can all be due to reverse causation, i.e. mild MS, or less disabling MS, may simply be associated with better lifestyle choices. It is unlikely that we are going to see Class 1 evidence anytime soon for these lifestyle factors, so it will need to be a judgement call you personally will need to take about whether or not to adopt them or not. Outside of MS there are strong scientific arguments to support a healthy lifestyle, which is why these factors are one of the pillars of our Brain Health campaign. The decision in my opinion, whether or not you have MS, is when are you going to take control of your own life and live the lifestyle that will optimise your long-term brain health? Your GP, neurologist or MS clinical nurse specialist can't do it for you."

OBJECTIVE: Emerging evidence links modifiable lifestyle risk factors to disease progression in multiple sclerosis (MS). We sought further evidence around this hypothesis through detailed analysis of the association with disability of lifestyle behaviours of a large international sample of people with MS.

CONCLUSIONS: Healthier lifestyle has strong associations with disability in our large international sample of people with MS, supporting further investigation into the role of lifestyle risk factors in MS disease progression.

OBJECTIVE: To prospectively investigate potential signs of pre-clinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort.METHODS: We linked the cognitive performance of all Norwegian men born in 1950-95 that underwent conscription examination at ages 18-19 to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study cognitive test-scores were available for 924/19530 male cases/controls. We estimated mean score differences among cases and controls and the risk of developing MS comparing lower to higher scores in strata of years to clinical onset.RESULTS: Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ=0.80, p=0.0095), corresponding to a 6 intelligence quotient (IQ)-points difference. Those scoring lowest, i.e. over 1 standard deviation below the controls' mean, had an increased MS risk during the two following years (relative risk=2.81, 95% confidence interval: 1.52-5.20). While results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored 4.6-6.9 IQ-points significantly lower than controls up to 20 years prior to first progressive symptoms.INTERPRETATION: RRMS may start years prior to clinical presentation and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease.

This study indicates that there may be problems with MS before diagnosis with MS, and you say....yes I know. I remember this or that happening, before I was diagnosed.

This study confirms that reported previously in Argentinian school children, where they looked at performance in maths tests years before diagnosis.

In this study the test was when Norwegian people were being conscripted to undertake their National Service that there may be subtle changes in the brains of people with MS before they get a diagnosis.

This is hardly surprising if we pay any attention to the migration studies (e.g. from low to high risk areas) and risk of MS. These suggest that you come into contact with the trigger before the age of fifteen. That most people do not get diagnosed until their mid twenties or later says that something must be going on for years before it is noticed.

Likewise we know about radiologically isolated syndrome, where people having a brain scan show up with MS lesions years before they get a clinical diagnosis.

Are you suffering from intractable constipation and faecal incontinence? #ClinicSpeak #MSResearch

"I forgot my rose-tinted spectacles at home. Some of you don't like the messy side of MS-related disability and if you are one of those please look away now."

"The paper below looks at the cost-effectiveness of transanal irrigation in patients with neurogenic bowel dysfunction. It comes as no surprise that transanal irrigation is a cost-saving treatment strategy reducing risk of stoma surgery, UTIs, episodes of faecal incontinence and improving quality of life in patients who have failed standard bowel care. It is important to realise that to remain independent MSers need to maintain upper limb and hand function. This is particularly important if you want to manage the anal irrigation system yourself. Anal irrigation is another reason to support our #ThinkHand campaign."

"I have posted many times in the past on constipation and bowel dysfunction, so many of you may find this, and other posts like it, repetitive. If you do have bowel problems and are not coping please contact your MS team for help; there is a lot we can do."

BACKGROUND: People suffering from neurogenic bowel dysfunction (NBD) and an ineffective bowel regimen often suffer from fecal incontinence (FI) and related symptoms, which have a huge impact on their quality of life. In these situations, transanal irrigation (TAI) has been shown to reduce these symptoms and improve quality of life.

AIM: To investigate the long-term cost-effectiveness of initiating TAI in patients with NBD who have failed standard bowel care (SBC).

METHODS: A deterministic Markov decision model was developed to project the lifetime health economic outcomes, including quality-adjusted life years (QALYs), episodes of FI, urinary tract infections (UTIs), and stoma surgery when initiating TAI relative to continuing SBC. A data set consisting of 227 patients with NBD due to spinal cord injury (SCI), multiple sclerosis, spina bifida and cauda equina syndrome was used in the analysis. In the model a 30-year old individual with SCI was used as a base-case. A probabilistic sensitivity analysis was applied to evaluate the robustness of the model.

RESULTS: The model predicts that a 30-year old SCI patient with a life expectancy of 37 years initiating TAI will experience a 36% reduction in FI episodes, a 29% reduction in UTIs, a 35% reduction in likelihood of stoma surgery and a 0.4 improvement in QALYs, compared with patients continuing SBC. A lifetime cost-saving of £21,768 per patient was estimated for TAI versus continuing SBC alone.

CONCLUSION: TAI is a cost-saving treatment strategy reducing risk of stoma surgery, UTIs, episodes of FI and improving QALYs for NBD patients who have failed SBC.

Friday, 26 August 2016

"For those of you with SPMS who thought you had been forgotten some great news yesterday. Siponimod, a S1P receptor modulator, has hit its primary outcome in the EXPAND SPMS trial. This is great news for the field and for the first time progressive MSers have treatment options. This also means that it is going to become very difficult doing new studies without comparing them to existing DMTs, in this case Siponimod, in the progressive MS space."

There are currently very limited treatment options for SPMS, a form of MS associated with gradual worsening of symptoms and accumulation of disability, independent of relapses.

EXPAND is the largest study ever conducted in SPMS, and is part of Novartis' ongoing leadership and commitment to people with MS.

Basel, August 25, 2016 - Novartis today announced the Phase III EXPAND study, evaluating the efficacy and safety of oral, once-daily, BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS), met its primary endpoint of a reduction in the risk of disability progression, compared with placebo. The EXPAND study represents the largest randomized, controlled study in SPMS to date.

"SPMS is a particularly disabling form of MS, and there is a need for effective treatment options to help delay disability progression in those living with the condition," said Vasant Narasimhan, Global Head of Drug Development and Chief Medical Officer for Novartis. "The positive EXPAND data are encouraging for a disease with such a high unmet need. We look forward to sharing the results at the upcoming ECTRIMS congress, and thank all of the study participants and investigators."

Topline results of the EXPAND study, including primary and key secondary endpoints, will be presented as a late breaking oral abstract at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 17th, in London, UK. Novartis will complete full analyses of the data and evaluate next steps in consultation with health authorities.

About the EXPAND study:

The EXPAND study is a randomized, double-blinded, placebo-controlled Phase III study, comparing the efficacy and safety of BAF312 versus placebo in people with secondary progressive multiple sclerosis (SPMS). The EXPAND study is the largest randomized, controlled study in SPMS to date. The study included 1,651 people with SPMS from 31 countries. Patients were randomized to receive either 2mg BAF312 or placebo in a 2:1 ratio respectively.

The primary endpoint of the study was an improvement in the time to three-month confirmed disability progression, as measured by the expanded disability status scale (EDSS), versus placebo. Secondary endpoints included delay in the time to six-month confirmed disability progression versus placebo, the time to confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW), T2 lesion volume, annualized relapse rate (ARR), and the safety and tolerability of BAF312 in people with SPMS.

About BAF312 (siponimod):

BAF312 (siponimod) is a selective modulator of specific types of the sphingosine-1-phosphate (S1P) receptor. The S1P receptor is commonly found on the surface of specific cells residing in the central nervous system (CNS), that are responsible for causing CNS damage that drives loss of function in secondary progressive MS (SPMS). BAF312 enters the brain and by binding to these specific receptors, may prevent the activation of these harmful cells, helping to reduce loss of physical and cognitive function associated with SPMS.

CoI: Prof G is a member of the EXPAND steering committee, Barts-MS participated in the EXPAND trial and DrK is the local principal investigator for the EXPAND study.

Does your neuroradiologist know how to distinguish between PML and MS? #ClinicSpeak #ResearchSpeak #MSBlog

"If you you are JCV-seropositive and are on natalizumab (Tysabri) you are at risk of developing PML. Depending on your how long you have been on natalizumab and your anti-JCV antibody index you may be having frequent MRI scans to monitor for early asymptomatic PML. The rationale is that if you pick-up PML very early before you have any symptoms and stop natalizumab you do much better in terms of outcome. The study below identifies characteristics of early PML lesions that distinguish then from new MS lesions. The presence of punctate T2 lesions, cortical grey matter involvement, white matter lesions next to the cortex, ill-defined and mixed lesion borders towards both grey and white matter, lesions larger than >3 cm in size and interestingly contrast enhancement were all associated with PML compared to new MS lesions. In contrast, well-defined focal lesions and localisation next to the ventricles were associated with new MS lesions. This findings are not trivial and I would encourage you to make sure that the neuroradiologist(s) who is/are reading your PML-surveillance scans have read this paper."

"What this paper does not describe is how rarely new T2 lesions develop on natalizumab treatment after the first 12 months. Another point worth mentioning is that now that we have so many treatment options if you are at high-risk of developing PML you really should consider transitioning onto another DMT. I know natalizumab is very effective drug, but we really should be trying to prevent any further cases of PML."

OBJECTIVE: Differentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation.

METHODS: Reference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters. We tested the association with PML for each characteristic and constructed a multivariable prediction model which we analysed using a receiver operating characteristic (ROC) curve.

INTERPRETATION: The MRI characteristics of asymptomatic natalizumab-associated PML lesions proved to differ from new MS lesions. This led to a prediction model with a high discriminating power. Careful assessment of the presence of punctate T2 lesions, cortical grey matter involvement, focal lesion appearance and periventricular localisation allows for an early diagnosis of PML.

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS.

They suggest that CTLA4 is an immunological checkpoint in the development of MS, that is, transition from subclinical RIS to CDMS as observed here.. This interpretation is further supported by 2 additional recent case reports.The first report describes a patient with pre-existing multiple sclerosis who had 2 clinical exacerbations and increased MRI activity shortly after initiation of ipilimumab for metastatic melanoma.The second report describes a 76-year-old patient who developed apparently de novo inflammatory CNS demyelination after treatment with ipilimumab for metastatic melanoma A third report describes a patient whose MS seemed to remain stable after treatment with ipilimumab for melanoma, but the tumor did not respond to ipilimumab, and the patient died due to melanoma progression.

Why does it not work in MS when it appears to work in animals?It is not clear but the T cell activation step may be occurring in the CNS and the infused antibody can't get into the CNS.However the antibody may not have to get into the brain in all cases.

Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.

In this study they blocked a receptor function on the blood vessels and it stopped white blood cell migrating into the CNS. However we know what happens when you block white blood cells getting into the brain, would this be the same?

Thursday, 25 August 2016

Never underestimate the power of imagination. #MSResearch #MSBlog #ClinicSpeak

"My brother-in-law who is a petrol head was a major Ayrton Senna fan and had the opportunity of meeting him. He told me that one of the reasons why Senna was so good is that he used motor imagery to practice; in addition to practising out on the track he used to spend hours, and hours, imaging racing on a particular track. He would mentally go through the gear changes, imagining the accelerations, decelerations and driving on and off the racing line. He told my brother-in-law that for every physical lap he practice he would 10 or more imaginary laps and he would vary the laps in his thoughts. He would even practice different overtaking manoeuvres in his mind. He claimed the mental imagery was what gave him the edge. I am, therefore, not surprised that cued motor imagery in relation to walking helps improve walking speed, fatigue and quality of life in MSers. I am not saying this can replace physical exercise, but it can augment it and all you need is a pair of headphones, music and an imagination. Easier said than done?"

RESULTS: Of the 112 participants randomised, 101 completed the study. Compared to controls, both interventions significantly improved walking speed, distance and perception. Significant improvements in cognitive but not psychosocial fatigue were seen in the intervention groups, and physical fatigue improved only in the music-based group. Both interventions improved QoL; however, music-cued motor imagery was superior at improving health-related QoL.

CONCLUSIONS: Rhythmic-cued motor imagery improves walking, fatigue and QoL in people with MS, with music-cued motor imagery being more effective.

OBJECTIVE:Analysis of the T-cell receptor (TCR) repertoire in the cerebrospinal fluid (CSF) of patients withmultiple sclerosis (MS) can reveal antigen-specific immune responses potentially implicated in the disease process. We applied a new unbiased deep-sequencing method for TCR repertoire analysis to accurately measure and compare receptor diversity and clonal expansions within the peripheral and CSF-trafficking T-cell populations of patients with MS and control individuals with idiopathic intracranial hypertension (IIH).METHODS:Paired blood and CSF TCR β-chain libraries from five MS patients and five IIH controls were sequenced, yielding a total of 80 million reads.RESULTS:Although TCR repertoire diversity was greater in the blood and CSF compartments of MS patients when compared with IIH controls, it is notable that the frequency of clonal expansions was also significantly higher in both compartments of MS patients. Highly expanded T-cell clones were enriched in the CSF compartment of MS patients compared to peripheral blood, very few of them were detected in both compartments.INTERPRETATION:Collectively, our data provide a proof of principle that private compartmentalized T-cell expansion exists in the intrathecal space of MS patients.

The target detecting molecules of a T cell is called the T cell receptor. If MS is autoimmune you would think that the disease causing cell would be expanded from the initial naive cell to the effector cell causing the disease. By sequencing the T cell receptor you can work out if two cells are clonal i.e. are the same because they come from the same originating cell. In this study they looked at the T cell receptor sequences and found that in MS there were evidence of expansions and there were expansions in the CNS, but are these the autoimmune?

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